The recent glory of the intestine

It has been known for centuries that our gut participates in the last stage of digestion and nourishes our body, letting through, through what we call the intestinal barrier, all the important components that our food brings us, proteins, sugars, lipids, vitamins and other trace elements that we do not know how to make and that our body needs every day.

For generations, it has also been known that the intestine, this digestive tract that is more than six meters long, contains what was until recently very poetically known as the intestinal flora – and that it is sensitive to antibiotics. , these drugs that kill bacteria. In order to reconstitute the intestinal flora after an antibiotic treatment, the doctor prescribes Ultra-Yeast and advises eating yogurts or similar dairy products because they contain micro-organisms.

During a gastro-enteritis, the intestine empties its contents but, after a few days, the flora is reconstituted and the organism can again take full advantage of the food that each meal brings to it. If the gastroenteritis persists, the doctor prescribes a stool culture – a stool analysis – which seeks to find in the intestinal flora which microbes known to be able to cause such a catastrophe could be introduced into the sick individual and cause the infection. This stool culture is done in a specialized laboratory and seeks to isolate the culprit germ. Often, it succeeds elsewhere … but not always, because this intestinal flora is a jungle called microbiota, composed of billions of bacteria, archaea, viruses, amoebae and other microorganisms, many of which are uncultivable and do not grow in conventional stool culture conditions. These are the subject of exciting recent discoveries that show in particular that the intestinal flora is not only for digestion!

The microbiota is an organ in itself that, in the early years of life, participates in the development of the body, plays a key role in the resistance to infections, establishes a very effective immune surveillance system. Even more surprisingly, it communicates with our brain, either by producing substances that migrate to it, via nerves or blood, or by stimulating the cells of the intestinal wall to produce compounds such as serotonin, a neurotransmitter that affects our psyche (it's an antidepressant) and also migrates to the brain.

A whole body of research has just opened, a new discipline has emerged – the general public has discovered it with "the discreet charm of the gut", the book of the German Giulia Enders, which was a huge bookstore success (see "Learn more"). It is a total upheaval in research laboratories, especially in basic or medical microbiology laboratories. Why ?

Genomics, metagenomics, bioinformatics: the actors of an incredible revolution

All living organisms have chromosomes (themselves made of DNA). The bacteria have only one, circular, twisted on itself, and, like all chromosomes, is made of a succession of genes that bacteria – and all living organisms – transmit to their offspring. We are talking about genetic heritage.

In the laboratories, for about forty years, the structure of the genes, and consequently the analysis of their function and their role – essential or accessory -, became possible thanks to techniques awarded by the Nobel Prize that the we call DNA sequencing or genomics. To do this, we grow the bacterium we are interested in, we "open" it by chemical means or ultrasound, isolate the genome and sequence. In the early 2000s, this exercise took about two years per bacterium and was extremely expensive (2 million euros for a bacterial genome). Technology has evolved so dramatically. Everything has become automated, the sequencing has become much faster – let's move on to the successive evolutions. We are now sequencing a bacterial genome in one day! And this for less than 1,000 euros.

But above all, thanks to the bioinformatics analysis, which has also progressed by leaps and bounds in a totally unpredictable way, it is no longer necessary to isolate the bacteria: we take a set of microorganisms – a microbiota -, we "open all" and we sequence without sorting. It is the computer that assembles the genomes or MAGs (metagenome-assembled genomes). This new era, that of metagenomics, began some ten years ago. The computer tool is able to inventory all or almost all the genomes present in a sample at a given time. A major advantage, this approach gives access to all the bacteria that can not be harvested that do not appear in classical stool cultures. Let's not forget that intestinal contents are strictly anaerobic and that many bacteria do not survive in the presence of oxygen.

Biodiversity: to each its microbiota!

While early microbiologists such as Pasteur and Koch sought to isolate the causative agent of a disease such as cholera or tuberculosis, scientists are now studying microbiota as a whole and their role in healthy men and women. the patients. It is a profusion of studies that show that the healthy man has set up his microbiota in the first years of his life, that many different species are present in the gut microbiota and that this great variety of species is a marker of good health and resistance to infections, but decreases with age. It can also become poorer in the case of a little varied diet and of course after treatment with antibiotics in series.

The composition of microbiota is becoming better known, and the differences between the populations of the most industrialized countries and those of countries or regions which are less so are becoming more clearly identified. We understand how the microbiota is influenced by various environmental parameters, such as the circadian rhythm – the 24-hour periodicity of human functions. In fact, night workers have intestinal problems due to changes in the composition of microbiota, changes that are also observed in people undergoing repeated time shifts, flight attendants and pilots. The alteration of the composition of the microbiota is called dysbiosis. Of course, in this recent discipline, distinguishing the cause of the consequences is still difficult. For example, we know that the microbiota of obese people is different from that of thin people, but is this difference due to an unbalanced diet, to genetic factors, or is obesity the result of this different composition of microbiota? ? Dysbiosis, if it becomes chronic and severe, can lead to inflammation of the intestinal tissue and serious intestinal diseases. Any imbalance should be avoided as it can lead to the proliferation of opportunistic bacteria that in normal circumstances are mere commensal bacteria. What scientists are looking for now is the respective roles of each species present, some with minor roles and others with essential roles.

Towards a manipulation of microbiota?

Given the importance of the gut microbiota, the idea was born to start manipulating microbiota either by indirect means by playing on nutrition – and the first results, especially in the field of obesity, are quite encouraging – or by performing fecal transplants. The latter gave very good results in the case of patients who had undergone an antibiotic treatment which had unfortunately led to the proliferation of a bacterium, Clostridium difficile, responsible for very tenacious gastroenteritis. It was found that a fecal transplant with a microbiota from a healthy person was successful in eradicating gastroenteritis. Work is under way in the case of babies born by cesarean section: the work shows that they have a much less rich flora than children born vaginally and that a fecal transplant enriches their flora.

The dawn of a personalized medicine

The microorganisms present in the gut microbiota play a very important role in the pharmacodynamics of all drugs, including in cancer treatments by chemotherapy or even immunotherapy. So we are in this extremely promising period when we can, after analyzing the microbiota of a patient, adapt the treatment that we want to prescribe according to bacteria and other microorganisms present. This future requires a very thorough knowledge of these compositions, knowledge that is far from complete, as shown by two articles published in February 2019. One describes, after analyzing 11,850 human microbiota, the discovery of 1,952 new bacteria. uncultivable so far. The other reports 4,930 new bacterial species, some of which do not even have a name yet. Yes, it is a whole new discipline and a new medicine that have just been born!